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Rho GDP Dissociation Inhibitor 2 Suppresses Metastasis via Unconventional Regulation of RhoGTPases

¹ Robert M. Berne Cardiovascular Research Center, ² Departments of Urology and Molecular Physiology and Biological Physics, ³ Departments of Microbiology, Cell Biology and Biomedical Engineering, and ⁴ Mellon Urologic Cancer Research Institute, University of Virginia, Charlottesville, Virginia

Requests for reprints: Martin A. Schwartz, Robert M. Berne Cardiovascular Research Center, University of Virginia, 415 Lane Road, MR5 Building, Room G111, Charlottesville, VA 22908. Phone: 434-243-4813; Fax: 434-924-2828; E-mail: maschwartz{at}virginia.edu.

Key Words: bladder cancer • Rho GTPase • metastasis • RhoGDI • Rac

Rho GDP dissociation inhibitor 2 (RhoGDI2) has been identified as a metastasis suppressor in bladder and possibly other cancers. This protein is a member of a family of proteins that maintain Rho GTPases in the cytoplasm and inhibit their activation and function. To understand the mechanism of metastasis suppression, we compared effects of RhoGDI1 and RhoGDI2. Despite showing much stronger inhibition of metastasis, RhoGDI2 is a weak inhibitor of Rho GTPase membrane targeting and function. However, point mutants that increase or decrease the affinity of RhoGDI2 for GTPases abolished its ability to inhibit metastasis. Surprisingly, metastasis suppression correlates with increased rather than decreased Rac1 activity. These data show that RhoGDI2 metastasis inhibition works through Rho GTPases but via a mechanism distinct from inhibition of membrane association. [Cancer Res 2009;69(7):2838–44]